PPARɣ Agonist Pioglitazone and Synthetic Surfactant Protein B Mimic B‐YL Prevents Hyperoxia‐Induced Lung Injury in Adult Mice

Surfactant protein B (SP-B) is an essential component of surfactant that promotes adsorption and spreading of surfactant phospholipids and stabilizes the phospholipid monolayer. SP-B is essential for respiratory function in newborn humans and mice; adult mice with levels of SP-B below 25% of wild-type develop fatal respiratory distress syndrome. A potential regulatory function of the C/A(−18) single nucleotide polymorphism (SNP) in the promoter of the SP-B gene was examined. Transcriptional analysis and ELISA on bronchoalveolar lavage fluid revealed that the presence of the C allele correlated with more SP-B promoter activity and protein. There was approximately threefold difference in amounts of SP-B in bronchoalveolar lavage fluid from CA(−18) and AA(−18) individuals. By EMSA, Sp1 bound more tightly to the C allele sequence than to the A allele sequence, perhaps accounting for the differences in transcription. Genotyping of a normal volunteer population showed ∼31% of the population were AA homozygotes, suggesting that these individuals produce less SP-B. Differences in amounts of SP-B resulting from the promoter SNP could affect the clinical presentation of pulmonary disease.

Download Full-text

Nitric oxide inhibits surfactant protein B gene expression in lung epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00084.2003 ◽

2003 ◽

Vol 285 (5) ◽

pp. L1153-L1165 ◽

Cited By ~ 17

Author(s):

Darrell Salinas ◽

Loretta Sparkman ◽

Kiflu Berhane ◽

Vijayakumar Boggaram

Keyword(s):

Gene Expression ◽

Nitric Oxide ◽

Epithelial Cells ◽

Lung Injury ◽

Surfactant Protein ◽

Mrna Levels ◽

Dependent Manner ◽

No Donors ◽

Surfactant Protein B ◽

Protein B

Surfactant protein B (SP-B) is an essential constituent of pulmonary surfactant. In a number of inflammatory diseases of the lung, elevated nitric oxide (NO) levels are associated with decreased SP-B levels, suggesting that reduced SP-B levels contribute to lung injury. In this study, we investigated the effects of NO on SP-B gene expression in H441 and MLE-12 cells, cell lines with characteristics of bronchiolar (Clara) and alveolar type II epithelial cells, respectively. Results show that NO donors decreased SP-B mRNA levels in a concentration- and time-dependent manner in H441 and MLE-12 cells. The NO donors also antagonized dexamethasone induction of SP-B mRNA in H441 cells. NO donor inhibition of SP-B mRNA was blocked by the transcriptional inhibitor 5,6-dichloro-1-β-d-ribofuranozyl-benzimidazole. NO donors decreased luciferase expression from a reporter plasmid containing -911/+41 bp of human SP-B 5′-flanking DNA in H441 and MLE-12 cells, indicating inhibitory effects on SP-B promoter activity. NO inhibition of SP-B mRNA levels was not blocked by LY-83583 and KT-5823, inhibitors of soluble guanylate cyclase and protein kinase G, respectively. Furthermore, cell-permeable cGMP analog 8-bromo-cGMP had no effect on SP-B mRNA levels. These data indicate that elevated NO levels negatively regulate SP-B gene expression by inhibiting gene transcription and that NO inhibits SP-B gene expression independently of cGMP levels. These data imply that reduced SP-B expression due to elevated NO levels can contribute to lung injury.

Download Full-text